Abstract
In a "one-pot" reaction, several transformations are carried out to form several bonds. Such reactions eliminate several purification steps, minimize the generation of chemical waste, and save time; thus, they can be viewed as "green" processes. However, there are several limitations in a one-pot reaction, and it cannot be considered as a simple connection of each optimized reaction. Dipeptidyl peptidase IV (DPP4, also known as CD26), a 110kDa serine protease that is ubiquitously distributed in the body, deactivates glucose-regulating hormones, such as GLP-1 and GIP. Thus, DPP4 inhibition has become a potential therapy for type 2 diabetes. ABT-341 (1) is a highly potent, selective, and orally bioavailable DPP4 inhibitor developed by Abbott Laboratories. An efficient, enantioselective total synthesis of ABT-341 (1) via single flask operation has been accomplished, demonstrating the power of asymmetric reactions catalyzed by organocatalysts, in particular diphenylprolinol silyl ether. The present synthesis has several noteworthy features: 1) the total yield is excellent (63 % from nitroalkene 4); 2) the synthesis consists of six reactions, which were conducted in a single flask; 3) four components were combined, to afford ABT-341 (1) in nearly equimolar amounts, except for inexpensive acetaldehyde (2 equiv.); 4) a disubstituted chiral cyclohexene carboxylate with the correct configuration was synthesized from three starting materials by successive reactions, including an asymmetric Michael reaction mediated by a diphenylprolinol silyl ether, as developed by our research group, a domino Michael reaction/Homer-Wadsworth-Emmons reaction combined with a retro-aldol reaction, and a base-catalyzed isomerization; 5) amide-bond formation and functional-group manipulations can also be performed chemoselectively in the same single flask by the appropriate choice of reaction conditions.
